The present invention relates to novel indolinones that inhibit receptor tyrosine kinases, their use as pharmaceuticals, particularly in the treatment of proliferative diseases, and pharmaceutical compositions comprising these compounds.
The present invention provides new indolinones of general formula 
substituted in the 6 position, the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof which have valuable properties.
The above compounds of general formula I wherein R1 denotes a hydrogen atom or a prodrug group have valuable pharmacological properties, in particular an inhibiting effect on various kinases, especially receptor tyrosine kinases such as VEGFR2, PDGFRxcex1, PDGFRxcex2, FGFR1, FGFR3, EGFR, HER2, IGF1R and HGFR, as well as complexes of CDK""s (Cyclin Dependent Kinases) such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9 with their specific cyclins (A, B1, B2, C, D1, D2, D3, E, F, G1, G2, H, I and K) and to viral cyclin (cf. L. Mengtao in J. Virology 71(3), 1984-1991 (1997)), and on the proliferation of cultivated human cells, in particular endothelial cells, e.g. in angiogenesis, but also on the proliferation of other cells, in particular tumour cells.
The other compounds of the above general formula I wherein R1 does not denote a hydrogen atom or a prodrug group are valuable intermediate products for preparing the abovementioned compounds.
The present invention thus relates to the above compounds of general formula I, whereby those compounds wherein R1 denotes a hydrogen atom or a prodrug group have valuable pharmacological properties, pharmaceutical compositions containing the pharmacologically active compounds, the use thereof and processes for preparing them.
In the above general formula I
X denotes an oxygen or sulphur atom,
R1 denotes a hydrogen atom or a prodrug group such as a C1-4-alkoxycarbonyl or C2-4-alkanoyl group,
R2 denotes a carboxy group, a straight-chain or branched C1-6-alkoxy-carbonyl group, a C4-7-cycloalkoxy-carbonyl or an aryloxycarbonyl group,
a straight-chain or branched C1-6-alkoxy-carbonyl group, which is terminally substituted in the alkyl moiety by a phenyl, heteroaryl, carboxy, C1-3-alkoxy-carbonyl, aminocarbonyl, C1-3-alkylamino-carbonyl or di-(C1-3-alkyl)-aminocarbonyl group,
a straight-chain or branched C2-6-alkoxy-carbonyl group, which is terminally substituted in the alkyl moiety by a chlorine atom or a hydroxy, C1-3-alkoxy, amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group,
an aminocarbonyl or methylaminocarbonyl group, an ethylaminocarbonyl group optionally substituted in the 2 position of the ethyl group by a hydroxy or C1-3-alkoxy group or, if R4 does not denote an aminosulphonyl-phenyl or Nxe2x80x94(C1-5-alkyl)-C1-3-alkylaminocarbonyl-phenyl group, it may also denote a di-(C1-2-alkyl)-aminocarbonyl group,
R3 denotes a hydrogen atom, a C1-6-alkyl, C3-7-cycloalkyl, trifluoromethyl or heteroaryl group,
a phenyl or naphthyl group, a phenyl or naphthyl group mono- or disubstituted by a fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl, C1-3-alkyl or C1-3-alkoxy group, whilst in the event of disubstitution the substituents may be identical or different and wherein the abovementioned unsubstituted as well as the mono- and disubstituted phenyl and naphthyl groups may additionally be substituted
by a hydroxy, hydroxy-C1-3-alkyl or C1-3-alkoxy-C1-3-alkyl group,
by a cyano, carboxy, carboxy-C1-3-alkyl, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylamino-carbonyl or di-(C1-3-alkyl)-aminocarbonyl group,
by a nitro group,
by an amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino or amino-C1-3-alkyl group,
by a C1-3-alkylcarbonylamino, Nxe2x80x94(C1-3-alkyl)-C1-3-alkyl-carbonylamino, C1-3-alkylcarbonylamino-C1-3-alkyl, Nxe2x80x94(C1-3-alkyl)-C1-3-alkylcarbonylamino-C1-3-alkyl, C1-3-alkyl-sulphonylamino,
C1-3-alkylsulphonylamino-C1-3-alkyl, Nxe2x80x94(C1-3-alkyl)-C1-3-alkylsulphonylamino-C1-3-alkyl or aryl-C1-3-alkylsulphonylamino group,
by a cycloalkylamino, cycloalkyleneimino, cycloalkyleneiminocarbonyl, cycloalkyleneimino-C1-3-alkyl, cycloalkyleneiminocarbonyl-C1-3-alkyl or cycloalkyleneiminosulphonyl-C1-3-alkyl group having 4 to 7 ring members in each case, whilst in each case the methylene group in position 4 of a 6- or 7-membered cycloalkyleneimino group may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, xe2x80x94NH or xe2x80x94N(C1-3-alkyl) group,
or by a heteroaryl or heteroaryl-C1-3-alkyl group,
R4 denotes a C3-7-cycloalkyl group,
whilst the methylene group in the 4 position of a 6- or 7-membered cycloalkyl group may be substituted by an amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group or replaced by an xe2x80x94NH or xe2x80x94N(C1-3-alkyl) group,
or a phenyl group substituted by the group R6, which may additionally be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C1-5-alkyl, trifluoromethyl, hydroxy, C1-3-alkoxy, carboxy, C1-3-alkoxycarbonyl, amino, acetylamino, C1-3-alkyl-sulphonylamnino, aminocarbonyl, C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, aminosulphonyl, C1-3-alkyl-aminosulphonyl, di-(C1-3-alkyl)-aminosulphonyl, nitro or cyano groups, wherein the substituents may be identical or different and wherein
R6 denotes a hydrogen, fluorine, chlorine, bromine or iodine atom,
a cyano, nitro, amino, C1-5-alkyl, C3-7-cycloalkyl, trifluoromethyl, phenyl, tetrazolyl or heteroaryl group,
the group of formula 
wherein the hydrogen atoms bound to a nitrogen atom may in each case be replaced independently of one another by a C1-3-alkyl group,
a C1-3-alkoxy group, a C1-3-alkoxy-C1-3-alkoxy, phenyl-C1-3-alkoxy, amino-C2-3-alkoxy, C1-3-alkylamino-C2-3-alkoxy, di-(C1-3-alkyl)-amino-C2-3-alkoxy, phenyl-C1-3-alkylamino-C2-3-alkoxy, Nxe2x80x94(C1-3-alkyl)-phenyl-C1-3-alkylamino-C2-3-alkoxy, C5-7-cycloalkyleneimino-C2-3-alkoxy or C1-3-alkylmercapto group,
a carboxy, C1-4-alkoxycarbonyl, aminocarbonyl, C1-3-alkylamino-carbonyl, Nxe2x80x94(C1-5-alkyl)-C1-3-alkylaminocarbonyl, phenyl-C1-3-alkylamino-carbonyl, Nxe2x80x94(C1-3-alkyl)-phenyl-C1-3-alkylamino-carbonyl, piperazinocarbonyl or Nxe2x80x94(C1-3-alkyl)-piperazinocarbonyl group,
a C1-3-alkylaminocarbonyl or Nxe2x80x94(C1-5-alkyl)-C1-3-alkylaminocarbonyl group wherein an alkyl moiety is substituted by a carboxy or C1-3-alkoxycarbonyl group or in the 2 or 3 position by a di-(C1-3-alkyl)amino, piperazino, Nxe2x80x94(C1-3-alkyl)-piperazino or a 4- to 7-membered cycloalkyleneimino group,
a C3-7-cycloalkyl-carbonyl group,
wherein the methylene group in the 4 position of the 6- or 7-membered cycloalkyl moiety may be substituted by an amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group or replaced by an xe2x80x94NH or xe2x80x94N(C1-3-alkyl) group,
a 4- to 7-membered cycloalkyleneimino group wherein
a methylene group linked to the imino group may be replaced by a carbonyl or sulphonyl group or
the cycloalkylene moiety may be fused to a phenyl ring or
one or two hydrogen atoms may each be replaced by a C1-3-alkyl group and/or
in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be substituted by a carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, phenyl-C1-3-alkylamino or Nxe2x80x94(C1-3-alkyl)-phenyl-C1-3-alkylamino group or
may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, xe2x80x94NH, xe2x80x94N(C1-3-alkyl), xe2x80x94N(phenyl), xe2x80x94N(C1-3-alkyl-carbonyl) or xe2x80x94N(benzoyl) group,
a C1-4-alkyl group substituted by the group R7, wherein
R7 denotes a C3-7-cycloalkyl group,
whilst the methylene group in the 4 position of a 6- or 7-membered cycloalkyl group may be substituted by an amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group or replaced by an xe2x80x94NH or xe2x80x94N(C1-3-alkyl) group or
in a 5- to 7-membered cycloalkyl group a xe2x80x94(CH2)2 group may be replaced by a xe2x80x94COxe2x80x94NH group, a xe2x80x94(CH2)3 group may be replaced by a xe2x80x94NHxe2x80x94COxe2x80x94NH or xe2x80x94COxe2x80x94NHxe2x80x94CO group or a xe2x80x94(CH2)4 group may be replaced by a xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94CO group, whilst in each case a hydrogen atom bound to a nitrogen atom may be replaced by a C1-3-alkyl group,
an aryl or heteroaryl group,
a hydroxy or C1-3-alkoxy group,
an amino, C1-7-alkylamino, di-(C1-7-alkyl)-amino, phenylamino, N-phenyl-C1-3-alkyl-amino, phenyl-C1-3-alkylamino, Nxe2x80x94(C1-3-alkyl)-phenyl-C1-3-alkylamino or di-(phenyl-C1-3-alkyl)-amino group,
an xcfx89-hydroxy-C2-3-alkyl-amino, Nxe2x80x94(C1-3-alkyl)-xcfx89-hydroxy-C2-3-alkyl-amino, di-(xcfx89-hydroxy-C2-3-alkyl)-amino, di-(xcfx89-(C1-3-alkoxy)-C2-3-alkyl)-amino or N-(dioxolan-2-yl)-C1-3-alkyl-amino group,
a C1-3-alkylcarbonylamino-C2-3-alkyl-amino or C1-3-alkylcarbonylamino-C2-3-alkyl-Nxe2x80x94(C1-3-alkyl)-amino group,
a C1-3-alkylsulphonylamino, Nxe2x80x94(C1-3-alkyl)-C1-3-alkylsulphonylamino, C1-3-alkylsulphonylamino-C2-3-alkyl-amino or C1-3-alkylsulphonylamino-C2-3-alkyl-Nxe2x80x94(C1-3-alkyl)-amino group,
a hydroxycarbonyl-C1-3-alkylamino or Nxe2x80x94(C1-3-alkyl)-hydroxycarbonyl-C1-3-alkyl-amino group,
a guanidino group wherein one or two hydrogen atoms may each be replaced by a C1-3-alkyl group,
a group of formula
xe2x80x94N(R8)xe2x80x94COxe2x80x94(CH2)nxe2x80x94R9xe2x80x83xe2x80x83(II),
xe2x80x83wherein
R8 denotes a hydrogen atom or a C1-3-alkyl group,
n denotes one of the numbers 0, 1, 2 or 3 and
R9 denotes an amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, phenylamino, Nxe2x80x94(C1-4-alkyl)-phenylamino, benzylamino, Nxe2x80x94(C1-4-alkyl)-benzylamino or C1-4-alkoxy group, a 4- to 7-membered cycloalkyleneimino group, whilst in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, xe2x80x94NH, xe2x80x94N(C1-3-alkyl), xe2x80x94N(phenyl), xe2x80x94N(C1-3-alkyl-carbonyl) or xe2x80x94N(benzoyl) group, or, if n denotes one of the numbers 1, 2 or 3, it may also denote a hydrogen atom,
a group of formula
xe2x80x94N(R10)xe2x80x94(CH2)mxe2x80x94(CO)oxe2x80x94R11xe2x80x83xe2x80x83(III),
xe2x80x83wherein
R10 denotes a hydrogen atom, a C1-3-alkyl group, a C1-3-alkylcarbonyl, arylcarbonyl, phenyl-C1-3-alkyl-carbonyl, C1-3-alkylsulphonyl, arylsulphonyl or phenyl-C1-3-alkylsulphonyl group,
m denotes one of the numbers 1, 2, 3 or 4,
o denotes the number 1 or, if m denotes one of the numbers 2, 3 or 4, o may also denote the number 0 and
R11 denotes an amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, phenylamino, Nxe2x80x94(C1-4-alkyl)-phenylamino, benzylamino, Nxe2x80x94(C1-4-alkyl)-benzylamino, C1-4-alkoxy or C1-3-alkoxy-C1-3-alkoxy group, a di-(C1-4-alkyl)-amino-C1-3-alkylamino group optionally substituted in the 1 position by a C1-3-alkyl group or a 4- to 7-membered cycloalkyleneimino group, wherein the cycloalkylene moiety may be fused to a phenyl ring or in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, xe2x80x94NH, xe2x80x94N(C1-3-alkyl), xe2x80x94N(phenyl), xe2x80x94N(C1-3-alkyl-carbonyl) or xe2x80x94N(benzoyl) group,
a C4-7-cycloalkylamino, C4-7-cycloalkyl-C1-3-alkylamino or C4-7-cycloalkenylamino group wherein position 1 of the ring is not involved in the double bond and wherein the abovementioned groups may each additionally be substituted at the amino-nitrogen atom by a C5-7-cycloalkyl, C2-4-alkenyl or C1-4-alkyl group,
a 4- to 7-membered cycloalkyleneimino group, wherein
the cycloalkylene moiety may be fused to a phenyl group or to an oxazolo, imidazolo, thiazolo, pyridino, pyrazino or pyrimidino group optionally substituted by a fluorine, chlorine, bromine or iodine atom, by a nitro, C1-3-alkyl, C1-3-alkoxy or amino group, and/or
one or two hydrogen atoms may each be replaced by a C1-3-alkyl, C5-7-cycloalkyl or phenyl group and/or
the methylene group in the 3 position of a 5-membered cycloalkyleneimino group may be substituted by a hydroxy, hydroxy-C1-3-alkyl, C1-3-alkoxy or C1-3-alkoxy-C1-3-alkyl group,
the methylene group in the 3 or 4 position of a 6- or 7-membered cycloalkyleneimino group may in each case be substituted by a hydroxy, hydroxy-C1-3-alkyl, C1-3-alkoxy, C1-3-alkoxy-C1-3-alkyl, carboxy, C1-4-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, phenyl-C1-3-alkylamino or Nxe2x80x94(C1-3-alkyl)-phenyl-C1-3-alkyl-amino group or
may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, xe2x80x94NH, xe2x80x94N(C1-3-alkyl-), xe2x80x94N(phenyl), xe2x80x94N(phenyl-C1-3-alkyl-), xe2x80x94N(C1-3-alkyl-carbonyl-), xe2x80x94N(C1-4-hydroxy-carbonyl-), xe2x80x94N(C1-4-alkoxy-carbonyl-), xe2x80x94N(benzoyl-) or xe2x80x94N(phenyl-C1-3-alkyl-carbonyl-) group,
wherein a methylene group linked to an imino-nitrogen atom of the cycloalkyleneimino group may be replaced by a carbonyl or sulphonyl group or in a 5- to 7-membered monocyclic cycloalkyleneimino group or a cycloalkyleneimino group fused to a phenyl group the two methylene groups linked to the imino-nitrogen atom may each be replaced by a carbonyl group,
or R6 denotes a C1-4-alkyl group which is substituted by a carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl or di-(C1-3-alkyl)-aminocarbonyl group or by a 4- to 7-membered cycloalkyleneiminocarbonyl group,
an Nxe2x80x94(C1-3-alkyl)-C2-4-alkanoylamino group) which is additionally substituted in the alkyl moiety by a carboxy or C1-3-alkoxycarbonyl group,
a group of formula
xe2x80x94N(R12)xe2x80x94COxe2x80x94(CH2)pxe2x80x94R13xe2x80x83xe2x80x83(IV),
xe2x80x83wherein
R12 denotes a hydrogen atom, a C1-6-alkyl or C3-7-cycloalkyl group or a C1-3-alkyl group terminally substituted by a phenyl, heteroaryl, trifluoromethyl, hydroxy, C1-3-alkoxy, aminocarbonyl, C1-4-alkylamino-carbonyl, di-(C1-4-alkyl)-amino-carbonyl, C1-3-alkyl-carbonyl, C1-3-alkyl-sulphonylamino,
Nxe2x80x94(C1-3-alkyl)-C1-3-alkyl-sulphonylamino, C1-3-alkyl-aminosulphonyl or di-(C1-3-alkyl)-aminosulphonyl group and
p denotes one of the numbers 0, 1, 2 or 3 and
R13 assumes the meanings of the abovementioned group R7, or, if p denotes one of the numbers 1, 2 or 3, it may also denote a hydrogen atom,
a group of formula
xe2x80x94N(R14)xe2x80x94(CH2)qxe2x80x94(CO)rxe2x80x94R15xe2x80x83xe2x80x83(V),
xe2x80x83wherein
R14 denotes a hydrogen atom, a C1-4-alkyl group, a C1-3-alkylcarbonyl, arylcarbonyl, phenyl-C1-3-alkylcarbonyl, heteroarylcarbonyl, heteroaryl-C1-3-alkylcarbonyl, C1-4-alkylsulphonyl, arylsulphonyl, phenyl-C1-3-alkylsulphonyl, heteroarylsulphonyl or heteroaryl-C1-3-alkyl-sulphonyl group,
q denotes one of the numbers 1, 2, 3 or 4,
r denotes the number 1 or, if q is one of the numbers 2, 3 or 4, it may also denote the number 0 and
R15 assumes the meanings of the abovementioned group R7,
a group of formula
xe2x80x94N(R16)xe2x80x94SO2xe2x80x94R17xe2x80x83xe2x80x83(VI),
xe2x80x83wherein
R16 denotes a hydrogen atom or a C1-4-alkyl group optionally terminally substituted by a cyano, trifluoromethyl-carbonylamino or Nxe2x80x94(C1-3-alkyl)-trifluoromethyl-carbonyl-amino group and
R17 denotes a C1-3-alkyl group,
an amino group substituted by a di-(C1-3-alkyl)-amino-C1-3-alkyl-carbonyl or di-(C1-3-alkyl)-amino-C1-3-alkyl-sulphonyl group and a di-(C1-3-alkyl)-aminocarbonyl-C1-3-alkyl group,
or an Nxe2x80x94(C1-3-alkyl)-C1-5-alkylsulphonylamino or Nxe2x80x94(C1-3-alkyl)-phenylsulphonylamino group wherein the alkyl moiety is additionally substituted by a cyano or carboxy group,
wherein all the single-bonded or fused phenyl groups contained in the groups mentioned under R6 may be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C1-5-alkyl, trifluoromethyl, hydroxy, C1-3-alkoxy, carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-4-alkylamino-carbonyl, di-(C1-4-alkyl)-amino-carbonyl, aminosulphonyl, C1-3-alkyl-aminosulphonyl, di-(C1-3-alkyl)-aminosulphonyl, C1-3-alkyl-sulphonylamino, nitro or cyano groups, wherein the substituents may be identical or different, or two adjacent hydrogen atoms of the phenyl groups may be replaced by a methylenedioxy group,
and
R5 denotes a hydrogen atom or a C1-3-alkyl group,
wherein by an aryl group is meant a phenyl or naphthyl group optionally mono- or disubstituted by a fluorine, chlorine, bromine or iodine atom, by a cyano, trifluoromethyl, nitro, carboxy, aminocarbonyl, C1-3-alkyl or C1-3-alkoxy group and
by a heteroaryl group is meant a monocyclic 5- or 6-membered heteroaryl group optionally substituted by a C1-3-alkyl group in the carbon skeleton, wherein
the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C1-3-alkyl or phenyl-C1-3-alkyl group, an oxygen or sulphur atom or
an imino group optionally substituted by a C1-3-alkyl or phenyl-C1-3-alkyl group or an oxygen or sulphur atom and additionally a nitrogen atom or
an imino group optionally substituted by a C1-3-alkyl or phenyl-C1-3-alkyl group and two nitrogen atoms,
and moreover a phenyl ring may be fused to the abovementioned monocyclic heterocyclic groups via two adjacent carbon atoms and the bonding takes place via a nitrogen atom or via a carbon atom of the heterocyclic moiety or a fused phenyl ring,
some or all of the hydrogen atoms in the abovementioned alkyl and alkoxy groups or in the alkyl moieties contained in the above-defined groups of formula I optionally being replaced by fluorine atoms,
the saturated alkyl and alkoxy moieties with more than 2 carbon atoms which are present in the groups defined hereinbefore also include the branched isomers thereof, such as for example the isopropyl, tert.butyl, isobutyl group, unless otherwise stated, and
additionally the hydrogen atom of any carboxy group present or a hydrogen atom bound to a nitrogen atom, e.g. a hydrogen atom of an amino, alkylamino or imino group or a saturated N-heterocycle such as the piperidinyl group, may each be replaced by a group which can be cleaved in vivo.
By a group which can be cleaved in vivo from an imino or amino group is meant, for example, a hydroxy group, an acyl group such as the benzoyl or pyridinoyl group or a C1-16-alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C1-16-alkoxycarbonyl group such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenyl-C1-6-alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a C1-3-alkylsulphonyl-C2-4-alkoxycarbonyl, C1-3-alkoxy-C2-4-alkoxy-C2-4-alkoxycarbonyl or ReCOxe2x80x94Oxe2x80x94(RfCRg)xe2x80x94Oxe2x80x94CO group wherein
Re denotes a C1-8-alkyl, C5-7-cycloalkyl, phenyl or phenyl-C1-3-alkyl group,
Rf denotes a hydrogen atom, a C1-3-alkyl, C5-7-cycloalkyl or phenyl group and
Rg denotes a hydrogen atom, a C1-3-alkyl or ReCOxe2x80x94Oxe2x80x94(RfCRg)xe2x80x94O group wherein Re to Rg are as hereinbefore defined,
wherein additionally the amino group may be a phthalimido group, whilst the abovementioned ester groups may also be used as a group which can be converted in vivo into a carboxy group.
One sub-group of compounds of general formula I which deserves special mention comprises those wherein
X, R1 and R3 to R5 are as hereinbefore defined and
R2 denotes a straight-chain or branched C1-6-alkoxy-carbonyl group, a C4-7-cycloalkoxycarbonyl or a aryloxycarbonyl group,
a straight-chain or branched C1-6-alkoxy-carbonyl group, which is terminally substituted in the alkyl moiety by a phenyl, heteroaryl, carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl or di-(C1-3-alkyl)-aminocarbonyl group,
a straight-chain or branched C2-6-alkoxy-carbonyl group, which is terminally substituted in the alkyl moiety by a chlorine atom or a hydroxy, C1-3-alkoxy, amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group,
the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof.
A second sub-group of compounds of general formula I which deserves special mention comprises those wherein
X, R1 and R3 to R5 are as hereinbefore defined and
R2 denotes an aminocarbonyl or methylaminocarbonyl group, an ethylaminocarbonyl group optionally substituted in the 2 position of the ethyl group by a hydroxy or C1-3-alkoxy group or, if R4 does not denote an aminosulphonyl-phenyl or Nxe2x80x94(C1-5-alkyl)-C1-3-alkylaminocarbonyl-phenyl group, R2 may also denote a di-(C1-2-alkyl)-aminocarbonyl group,
the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof.
A third sub-group of compounds of general formula I which deserves special mention comprises those wherein
X, R1 to R3 and R5 are as hereinbefore defined and
R4 denotes an R7xe2x80x94(C1-4-alkyl)-phenyl group, wherein
R7 denotes an amino, C1-7-alkylamino, di-(C1-7-alkyl)-amino, phenylamino, N-phenyl-C1-3-alkyl-amino, phenyl-C1-3-alkylamino, Nxe2x80x94(C1-3-alkyl)-phenyl-C1-3-alkylamino or di-(phenyl-C1-3-alkyl)-amino group,
or a phenyl group substituted by the group of formula
xe2x80x94N(R12)xe2x80x94COxe2x80x94(CH2)pxe2x80x94R13xe2x80x83xe2x80x83(IV),
wherein R12, p and R13 are as hereinbefore defined,
the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof.
Preferred compounds of general formula I are those wherein
R1 and R3 are as hereinbefore defined and
X denotes an oxygen atom,
R2 denotes a carboxy group, a straight-chain or branched C1-6-alkoxy-carbonyl group, a C5-7-cycloalkoxycarbonyl or a phenoxycarbonyl group,
a straight-chain or branched C1-3-alkoxy-carbonyl group, which is terminally substituted in the alkyl moiety by a phenyl, heteroaryl, carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl or di-(C1-3-alkyl)-aminocarbonyl group,
a straight-chain or branched C2-3-alkoxy-carbonyl group, which is terminally substituted in the alkyl moiety by a chlorine atom, by a hydroxy, C1-3-alkoxy, amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group,
an aminocarbonyl or methylaminocarbonyl group, an ethylaminocarbonyl group optionally substituted in the 2 position of the ethyl group by a hydroxy or C1-3-alkoxy group or, if R4 does not denote an aminosulphonyl-phenyl or Nxe2x80x94(C1-5-alkyl)-C1-3-alkylaminocarbonyl-phenyl group, it may also denote a di-(C1-2-alkyl)-aminocarbonyl group,
R4 denotes a C3-7-cycloalkyl group,
whilst the methylene group in the 4 position of a 6 or 7-membered cycloalkyl group may be substituted by an amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group or replaced by an xe2x80x94NH or xe2x80x94N(C1-3-alkyl) group,
or a phenyl group substituted by the group R6, which may additionally be mono- or disubstituted by fluorine, chlorine or bromine atoms, by C1-3-alkyl, trifluoromethyl, hydroxy, C1-3-alkoxy, carboxy, C1-3-alkoxycarbonyl, amino, acetylamino, aminocarbonyl, C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, nitro or cyano groups, wherein the substituents may be identical or different and wherein
R6 denotes a hydrogen, fluorine, chlorine, bromine or iodine atom,
a cyano, nitro, amino, C1-5-alkyl, C3-7-cycloalkyl, trifluoromethyl, phenyl, tetrazolyl or heteroaryl group,
the group of formula 
wherein a hydrogen atom bound to the nitrogen atom may be replaced by a C1-3-alkyl group,
a C1-3-alkoxy group, an amino-C2-3-alkoxy, C1-3-alkylamino-C2-3-alkoxy, di-(C1-3-alkyl)-amino-C2-3-alkoxy, phenyl-C1-3-alkylamino-C2-3-alkoxy, Nxe2x80x94(C1-3-alkyl)-phenyl-C1-3-alkylamino-C2-3-alkoxy, pyrrolidino-C2-3-alkoxy, piperidino-C2-3-alkoxy or C1-3-alkylmercapto group,
a carboxy, C1-4-alkoxycarbonyl, aminocarbonyl, C1-3-alkylamino-carbonyl, phenyl-C1-3-alkylamino-carbonyl or Nxe2x80x94(C1-3-alkyl)-phenyl-C1-3-alkylamino-carbonyl group,
a C3-7-cycloalkyl-carbonyl group,
wherein the methylene group in the 4 position of the 6- or 7-membered cycloalkyl moiety may be replaced by an xe2x80x94NH or xe2x80x94N(C1-3-alkyl) group,
a 4- to 7-membered cycloalkyleneimino group, wherein
a methylene group linked to the imino group may be replaced by a carbonyl or sulphonyl group or
one or two hydrogen atoms may each be replaced by a C1-3-alkyl group and/or
in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be substituted by a carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, phenyl-C1-3-alkylamino or Nxe2x80x94(C1-3-alkyl)-phenyl-C1-3-alkylamino group or
may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, xe2x80x94NH or xe2x80x94N(C1-3-alkyl) group,
a C1-4-alkyl group terminally substituted by the group R7, wherein
R7 denotes a C5-7-cycloalkyl group,
whilst the methylene group in the 4 position of a 6- or 7-membered cycloalkyl group may be replaced by an xe2x80x94NH or xe2x80x94N(C1-3-alkyl) group or
in a 5- to 7-membered cycloalkyl group a xe2x80x94(CH2)2 group may be replaced by a xe2x80x94COxe2x80x94NH group, a xe2x80x94(CH2)3 group may be replaced by a xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94 or a xe2x80x94(CH2)4 group may be replaced by a xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94CO group, whilst in each case a hydrogen atom bound to a nitrogen atom may be replaced by a C1-3-alkyl group,
a phenyl or heteroaryl group,
a hydroxy or C1-3-alkoxy group,
an amino, C1-6-alkylamino, di-(C1-6-alkyl)-amino, phenylamino, N-phenyl-C1-3-alkylamino, phenyl-C1-3-alkylamino, Nxe2x80x94(C1-3-alkyl)-phenyl-C1-3-alkylamino or di-(phenyl-C1-3-alkyl)-amino group,
a xcfx89-hydroxy-C2-3-alkyl-amino, Nxe2x80x94(C1-3-alkyl)-xcfx89-hydroxy-C2-3-alkyl-amino, di-(xcfx89-hydroxy-C2-3-alkyl)-amino, di-(xcfx89-(C1-3-alkoxy)-C2-3-alkyl)-amino or Nxe2x80x94(dioxolan-2-yl)-C1-3-alkyl-amino group,
a C1-3-alkylcarbonylamino-C2-3-alkyl-amino or C1-3-alkylcarbonylamino-C2-3-alkyl-Nxe2x80x94(C1-3-alkyl)-amino group,
a C1-3-alkylsulphonylamino, Nxe2x80x94(C1-3-alkyl)-C1-3-alkylsulphonylamino, C1-3-alkylsulphonylamino-C2-3-alkyl-amino or C1-3-alkylsulphonylamino-C2-3-alkyl-Nxe2x80x94(C1-3-alkyl)amino group,
a hydroxycarbonyl-C1-3-alkylamino or Nxe2x80x94(C1-3-alkyl)-hydroxycarbonyl-C1-3-alkyl-amino group
a guanidino group wherein a hydrogen atom may be replaced by a C1-3-alkyl group,
a group of formula
xe2x80x94N(R8)xe2x80x94COxe2x80x94(CH2)nxe2x80x94R9xe2x80x83xe2x80x83(II),
xe2x80x83wherein
R8 denotes a hydrogen atom or a C1-3-alkyl group,
n denotes one of the numbers 0, 1, 2 or 3 and
R9 denotes an amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, phenylamino, benzylamino or C1-4-alkoxy group, a 5- to 7-membered cycloalkyleneimino group, wherein the methylene group in position 4 of the piperidino group may be replaced by an oxygen or sulphur atom, by an xe2x80x94NH, xe2x80x94N(C1-3-alkyl), xe2x80x94N(phenyl), xe2x80x94N(C1-3-alkyl-carbonyl) or xe2x80x94N(benzoyl) group, or, if n denotes one of the numbers 1, 2 or 3, it may also denote a hydrogen atom,
a group of formula
xe2x80x94N(R10)xe2x80x94(CH2)mxe2x80x94(CO)oxe2x80x94R11xe2x80x83xe2x80x83(III),
xe2x80x83wherein
R10 denotes a hydrogen atom, a C1-3-alkyl group, a C1-3-alkylcarbonyl or C1-3-alkylsulphonyl group,
m denotes one of the numbers 1, 2 or 3,
o denotes the number 1 or, if m is one of the numbers 2 or 3, o may also denote the number 0 and
R11 denotes an amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, C1-4-alkoxy or C1-3-alkoxy-C1-3-alkoxy group or a 5- to 7-membered cycloalkyleneimino group, wherein the methylene group in position 4 of the piperidino group may be replaced by an oxygen or sulphur atom, by an xe2x80x94NH, xe2x80x94N(C1-3-alkyl), xe2x80x94N(phenyl), xe2x80x94N(C1-3-alkyl-carbonyl) or xe2x80x94N(benzoyl) group,
a C4-7-cycloalkylamino or C4-7cycloalkenylamino group wherein position 1 of the ring is not involved in the double bond,
a 4- to 7-membered cycloalkyleneimino group, wherein
the cycloalkylene moiety may be fused to a phenyl group or
one or two hydrogen atoms may each be replaced by a C1-3-alkyl group and/or
the methylene group in position 3 of the pyrrolidino group may be substituted by a hydroxy or C1-3-alkoxy group,
in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be substituted by a hydroxy, hydroxy-C1-3-alkyl, C1-3-alkoxy, carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, phenyl-C1-3-alkylamino or Nxe2x80x94(C1-3-alkyl)-phenyl-C1-3-alkylamino group or
may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, xe2x80x94NH, xe2x80x94N(C1-3-alkyl), xe2x80x94N(phenyl), xe2x80x94N(phenyl-C1-3-alkyl), xe2x80x94N(C1-3-alkyl-carbonyl), xe2x80x94N(C1-4-alkoxy-carbonyl), xe2x80x94N(benzoyl) or xe2x80x94N(phenyl-C1-3-alkyl-carbonyl) group,
wherein a methylene group linked to an imino-nitrogen atom of the cycloalkyleneimino group may be replaced by a carbonyl or sulphonyl group or in a 5- to 6-membered monocyclic cycloalkyleneimino group or a cycloalkyleneimino group fused to a phenyl group the two methylene groups linked to the imino-nitrogen atom may each be replaced by a carbonyl group,
or R6 denotes a C1-4-alkyl group which is terminally substituted by a carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl or di-(C1-3-alkyl)-aminocarbonyl group or by a 4- to 7-membered cycloalkyleneiminocarbonyl group,
a group of formula
xe2x80x94N(R12)xe2x80x94COxe2x80x94(CH2)pxe2x80x94R13xe2x80x83xe2x80x83(IV),
xe2x80x83wherein
R12 denotes a hydrogen atom, a C1-3-alkyl, C5-7-cycloalkyl, phenyl-C1-3-alkyl or heteroaryl-C1-3-alkyl group and
p denotes one of the numbers 0, 1, 2 or 3 and
R13 assumes the meanings of the abovementioned group R7, or, if p denotes one of the numbers 1, 2 or 3, it may also denote a hydrogen atom,
a group of formula
xe2x80x94N(R14)xe2x80x94(CH2)qxe2x80x94(CO)rxe2x80x94R15xe2x80x83xe2x80x83(V),
xe2x80x83wherein
R14 denotes a hydrogen atom, a C1-4-alkyl group, a C1-3-alkylcarbonyl, phenylcarbonyl, phenyl-C1-3-alkylcarbonyl, heteroarylcarbonyl, heteroaryl-C1-3-alkylcarbonyl, C1-4-alkylsulphonyl, phenylsulphonyl, phenyl-C1-3-alkylsulphonyl- heteroarylsulphonyl or heteroaryl-C1-3-alkyl-sulphonyl group,
q denotes one of the numbers 1, 2, 3 or 4,
r denotes the number 1 or, if q is one of the numbers 2, 3 or 4, it may also denote the number 0 and
R15 assumes the meanings of the abovementioned group R7,
a group of formula
xe2x80x94N(R16)xe2x80x94SO2xe2x80x94R17xe2x80x83xe2x80x83(VI),
xe2x80x83wherein
R16 denotes a hydrogen atom or a C1-4-alkyl group optionally terminally substituted by a cyano, trifluoromethyl-carbonylamino or Nxe2x80x94(C1-3-alkyl)-trifluoromethyl-carbonyl-amino group and
R17 denotes a C1-3-alkyl group,
an amino group substituted by a di-(C1-3-alkyl)-amino-C1-3-alkyl-carbonyl or di-(C1-3-amino-C1-3-alkyl-sulphonyl group and a di-(C1-3-alkyl)-aminocarbonyl-C1-3-alkyl group,
wherein all the single-bonded or fused phenyl groups contained in the groups mentioned under R6 may be mono- or disubstituted by fluorine, chlorine or bromine atoms, by C1-3-alkyl, trifluoromethyl, hydroxy, C1-3-alkoxy, carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkyl-aminocarbonyl, aminosulphonyl, C1-3-alkyl-aminosulphonyl, nitro or cyano groups, wherein the substituents may be identical or different, or two adjacent hydrogen atoms of the phenyl groups may be replaced by a methylenedioxy group, and
R5 denotes a hydrogen atom or a C1-3-alkyl group,
whilst by a heteroaryl group as mentioned above is meant a pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl or triazolyl group optionally substituted in the carbon skeleton by a C1-3-alkyl group wherein a hydrogen atom bound to a nitrogen atom may be replaced by a C1-3-alkyl or phenyl-C1-3-alkyl group and wherein the 5-membered heteroaryl groups containing at least one imino group are bound via a carbon or nitrogen atom,
a hydrogen atom bound to a nitrogen atom in the abovementioned groups may be replaced by a group which can be cleaved in vivo, particularly by an acetyl or tert.butoxycarbonyl group,
the carboxy groups contained in the abovementioned groups may each be substituted by a group which can be cleaved in vivo and may occur, for example, in the form of the tert.butoxycarbonyl group,
some or all of the hydrogen atoms in the abovementioned alkyl and alkoxy groups or in the alkyl moieties contained in the above-defined groups of formula I optionally being replaced by fluorine atoms and
the saturated alkyl and alkoxy moieties contained in the abovementioned groups, which contain more than 2 carbon atoms, may be straight-chain or branched, unless otherwise stated,
the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof.
One subgroup of preferred compounds of general formula I deserving special mention comprises those wherein
X, R1 and R3 to R5 are as hereinbefore defined and
R2 denotes a straight-chain or branched C1-6alkoxy-carbonyl group, a C5-7-cycloalkoxycarbonyl or a phenoxycarbonyl group,
a straight-chain or branched C1-3-alkoxy-carbonyl group, which is terminally substituted in the alkyl moiety by a phenyl-carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl or di-(C1-3-alkyl)-aminocarbonyl group,
a straight-chain or branched C2-3-alkoxy-carbonyl group, which is terminally substituted in the alkyl moiety by a hydroxy, C1-3-alkoxy, amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group,
the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof.
A second sub-group of preferred compounds of general formula l deserving special mention comprises those wherein
X, R1 and R3 to R5 are as hereinbefore defined and
R2 denotes an aminocarbonyl or methylaminocarbonyl group, an ethylaminocarbonyl group optionally substituted in the 2 position of the ethyl group by a hydroxy or C1-3-alkoxy group or, if R4 does not denote an aminosulphonyl-phenyl or Nxe2x80x94(C1-5-alkyl)-C1-3-alkylaminocarbonyl-phenyl group, R2 may also denote a di-(C1-2-alkyl)-aminocarbonyl group,
the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof.
A third sub-group of preferred compounds of general formula I deserving special mention comprises those wherein
X, R1 to R3 and R5 are as hereinbefore defined and
R4 denotes an R7-(n-C1-4-alkyl)-phenyl group, wherein
R7 denotes an amino, C1-6-alkylamino, di-(C1-6-alkyl)-amino, phenylamino, N-phenyl-C1-3-alkyl-amino, phenyl-C1-3-alkylamino, Nxe2x80x94(C1-3-alkyl)-phenyl-C1-3-alkylamino or di-(phenyl-C1-3-alkyl)-amino group,
or a phenyl group substituted by the group of formula
xe2x80x94N(R12)xe2x80x94COxe2x80x94(CH2)pxe2x80x94R13xe2x80x83xe2x80x83(IV),
wherein R12, p and R13 are as hereinbefore defined,
the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof.
Particularly preferred compounds of general formula I are those wherein
X denotes an oxygen atom,
R1 denotes a hydrogen atom,
R2 denotes a carboxy group, a straight-chain or branched C1-4-alkoxycarbonyl group or a phenoxycarbonyl group,
a straight-chain or branched C1-3-alkoxycarbonyl group, which is terminally substituted in the alkyl moiety by a phenyl, carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl or di-(C1-3-alkyl)-aminocarbonyl group,
a straight-chain or branched C2-3-alkoxy-carbonyl group which is terminally substituted in the alkyl moiety by a hydroxy, C1-3-alkoxy, amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group,
an aminocarbonyl or methylaminocarbonyl group, an ethylaminocarbonyl group optionally substituted in the 2 position of the ethyl group by a hydroxy or C1-3-alkoxy group or, if R4 does not denote an aminosulphonyl-phenyl or Nxe2x80x94(C1-5-alkyl)-C1-3-alkylaminocarbonyl-phenyl group, it may also denote a di-(C1-2-alkyl)-aminocarbonyl group,
R3 denotes a C1-4-alkyl group or a phenyl group which may be substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C1-3-alkyl, hydroxy or C1-3-alkoxy group,
R4 denotes a C5-6cycloalkyl group,
wherein the methylene group in position 4 of the cyclohexyl group may be substituted by an amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group or replaced by an xe2x80x94NH or xe2x80x94N(C1-3-alkyl) group,
a phenyl group, a phenyl group disubstituted by C1-3-alkyl, C1-3-alkoxy or nitro groups, wherein the substituents may be identical or different, or
a phenyl group substituted by the group R6, which may additionally be substituted by a fluorine, chlorine or bromine atom or by an amino or nitro group, wherein R6 denotes a fluorine, chlorine or bromine atom,
a C1-3-alkyl, C1-3-alkoxy, nitro, amino or C5-6-cycloalkyl group,
a pyrrolyl, pyrazolyl, imidazolyl, triazolyl or tetrazolyl group bound via a carbon atom, wherein the abovementioned heteroaromatic groups in the carbon skeleton may be substituted by a C1-3-alkyl group or a hydrogen atom bound to a nitrogen atom may be replaced by a C1-3-alkyl or phenyl-C1-3-alkyl group,
the group of formula 
a carboxy, C1-4-alkoxycarbonyl, phenyl-C1-3-alkylamino-carbonyl or C5-7-cycloalkyl-carbonyl group,
a 5 or 6-membered cycloalkyleneimino group, wherein
the methylene group in position 4 of the piperidino group may be replaced by an oxygen or sulphur atom, by an xe2x80x94NH or xe2x80x94N(C1-3-alkyl) group,
an unbranched C1-3-alkyl group terminally substituted by the group R7, wherein
R7 denotes a C5-7-cycloalkyl group,
wherein in a 5 or 6-membered cycloalkyl group a xe2x80x94(CH2)2 group may be replaced by a xe2x80x94COxe2x80x94NH group, a CH2)3 group may be replaced by an xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94 or a xe2x80x94(CH2)4 group may be replaced by an xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94CO group, whilst in each case a hydrogen atom bound to a nitrogen atom may be replaced by a C1-3-alkyl group,
a phenyl or pyridinyl group or a pyrrolyl, pyrazolyl, imidazolyl or triazolyl group bound via a carbon or nitrogen atom, wherein the abovementioned heteroaromatic groups in the carbon skeleton may be substituted by a C1-3-alkyl group or a hydrogen atom bound to a nitrogen atom may be replaced by a C1-3-alkyl group,
a hydroxy or C1-3-alkoxy group,
an amino, C1-6-alkylamino, di-(C1-6-alkyl)-amino, phenylamino, N-phenyl-C1-3-alkylamino, phenyl-C1-3-alkylamino or Nxe2x80x94(C1-3-alkyl)-phenyl-C1-3-alkylamino group,
a xcfx89-hydroxy-C2-3-alkyl-amino, Nxe2x80x94(C1-3-alkyl)-xcfx89-hydroxy-C2-3-alkylamino, di-(xcfx89-hydroxy-C2-3-alkyl)-amino or di-(xcfx89-(C1-3-alkoxy)-C2-3-alkyl)-amino group,
a C1-3-alkylcarbonylamino-C2-3-alkyl-amino or C1-3-alkylcarbonylamino-C2-3-alkyl-Nxe2x80x94(C1-3-alkyl)-amino group,
a C1-3-alkylsulphonylamino, Nxe2x80x94(C1-3-alkyl)-C1-3-alkylsulphonylamino, C1-3-alkylsulphonylamino-C2-3-alkylamino or C1-3-alkylsulphonylamino-C2-3-alkyl-Nxe2x80x94(C1-3-alkyl)-amino group,
a hydroxycarbonyl-C1-3-alkylamino or Nxe2x80x94(C1-3-alkyl)-hydroxycarbonyl-C1-3-alkyl-amino group,
a guanidino group wherein a hydrogen atom may be replaced by a C1-3-alkyl group,
a group of formula
xe2x80x94N(R8)xe2x80x94COxe2x80x94(CH2)nxe2x80x94R9xe2x80x83xe2x80x83(II),
xe2x80x83wherein
R8 denotes a hydrogen atom or a C1-3-alkyl group,
n denotes one of the numbers 0, 1, 2 or 3 and
R9 denotes an amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino or C1-4-alkoxy group, a 5- or 6-membered cycloalkyleneimino group, wherein the methylene group in position 4 of the piperidino group may be replaced by an xe2x80x94NH, xe2x80x94N(C1-3-alkyl) or xe2x80x94N(C1-3-alkyl-carbonyl) group, or, if n denotes one of the numbers 1, 2 or 3, R9 may also denote a hydrogen atom,
a group of formula
xe2x80x94N(R10)xe2x80x94(CH2)mxe2x80x94(CO)oxe2x80x94R11xe2x80x83xe2x80x83(III),
xe2x80x83wherein
R10 denotes a hydrogen atom or a C1-3-alkyl group,
m denotes one of the numbers 1, 2 or 3,
o denotes the number 1 or, if m is one of the numbers 2 or 3, o may also denote the number 0 and
R11 denotes an amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, C1-4-alkoxy or methoxy-C1-3-alkoxy group or a 5- or 6-membered cycloalkyleneimino group, wherein the methylene group in position 4 of the piperidino group may be replaced by an xe2x80x94NH, xe2x80x94N(C1-3-alkyl) or xe2x80x94N(C1-3-alkyl-carbonyl) group,
an azetidino, pyrrolidino, piperidino, 2,6-dimethyl-piperidino, 3,5-dimethyl-piperidino or azepino group, wherein
the methylene group in position 3 of the pyrrolidino group may be substituted by a hydroxy group,
the methylene group in position 4 of the piperidino group may be substituted by a hydroxy, hydroxy-C1-3-alkyl or C1-3-alkoxy group or
may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, xe2x80x94NH, xe2x80x94N(C1-3-alkyl), xe2x80x94N(C1-3-alkyl-carbonyl), xe2x80x94N(benzoyl) or xe2x80x94N(phenyl-C1-3-alkyl-carbonyl) group,
wherein a methylene group linked to an imino-nitrogen atom of the pyrrolidino, piperidino or piperazino group may be replaced by a carbonyl group,
or R6 denotes a straight-chain C1-3-alkyl group which is terminally substituted by a carboxy or C1-3-alkoxy-carbonyl group,
a group of formula
xe2x80x94N(R12)xe2x80x94COxe2x80x94(CH2)pxe2x80x94R13xe2x80x83xe2x80x83(IV),
xe2x80x83wherein
R12 denotes a hydrogen atom, a C1-3-alkyl or phenyl-C1-3-alkyl group,
p denotes one of the numbers 0, 1 or 2 and
R13 denotes an amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, benzylamino, Nxe2x80x94(C1-3-alkyl)-benzylamino, C1-3-alkoxy-C1-3-alkylamino, Nxe2x80x94(C1-3-alkyl)-C1-3-alkoxy-C1-3-alkylamino, di-(2-methoxy-ethyl)-amino, di-(xcfx89-hydroxy-C2-3-alkyl)-amino or aminocarbonyl-methyl-N-(methyl)-amino group,
a pyrrolyl, pyrazolyl or imidazolyl group bound via a nitrogen atom and optionally substituted by a C1-3-alkyl group,
a pyrrolidino, piperidino, morpholino, thiomorpholino or a piperazino group optionally substituted in the 4 position by a C1-3-alkyl, phenyl-C1-3-alkyl, C1-3-alkylcarbonyl or C1-4-alkoxycarbonyl group or, if n denotes the number 1 or 2, it may also denote a hydrogen atom,
a group of formula
xe2x80x94N(R14)xe2x80x94(CH2)qxe2x80x94(CO)rxe2x80x94R15xe2x80x83xe2x80x83(V),
xe2x80x83wherein
R14 denotes a hydrogen atom, a C1-4-alkyl, C1-3-alkyl-carbonyl, phenylcarbonyl, phenyl-C1-3-alkylcarbonyl, furyl-carbonyl, pyridinyl-carbonyl, furyl-C1-3-alkyl-carbonyl, pyridinyl-C1-3-alkylcarbonyl, C1-4-alkylsulphonyl, phenylsulphonyl or phenyl-C1-3-alkylsulphonyl group,
q denotes one of the numbers 1, 2 or 3,
r denotes the number 1 or, if q is one of the numbers 2 or 3, it may also denote the number 0 and
R15 denotes an amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, phenylamino, Nxe2x80x94(C1-4-alkyl)-phenylamino, benzylamino or Nxe2x80x94(C1-4-alkyl)-benzylamino group,
or a group of formula
xe2x80x94N(R16)xe2x80x94SO2xe2x80x94R17xe2x80x83xe2x80x83(VI),
xe2x80x83wherein
R16 denotes a hydrogen atom or a C1-3-alkyl group optionally terminally substituted by a cyano, trifluoromethyl-carbonylamino or Nxe2x80x94(C1-3-alkyl)-trifluoromethyl-carbonyl-amino group and
R17 denotes a C1-3-alkyl group,
wherein all the single-bonded or fused phenyl groups contained in the groups mentioned under R6 may be substituted by a fluorine, chlorine or bromine atom, by a methyl, trifluoromethyl, methoxy, nitro or cyano group and
R5 denotes a hydrogen atom,
wherein a hydrogen atom bound to a nitrogen atom in the abovementioned groups may be replaced by an acetyl or tert.butoxycarbonyl group,
the carboxy groups contained in the abovementioned groups may also be present in the form of the tert.butoxycarbonyl precursor group and
the saturated alkyl and alkoxy moieties contained in the abovementioned groups, which contain more than 2 carbon atoms, may be straight-chain or branched, unless otherwise stated,
the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof.
One subgroup of particularly preferred compounds of general formula I deserving special mention comprises those wherein
X, R1, R3 and R5 are as hereinbefore defined,
R2 denotes a straight-chain or branched C1-4-alkoxycarbonyl group or a phenoxycarbonyl group,
a straight-chain or branched C1-3-alkoxycarbonyl group, which is terminally substituted in the alkyl moiety by a phenyl-carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl or di-(C1-3-alkyl)-aminocarbonyl group, or
a straight-chain or branched C2-3-alkoxy-carbonyl group, which is terminally substituted in the alkyl moiety by a hydroxy, C1-3-alkoxy, amino, C1-3-alkylamino or di-(C1-3-alkylamino group, and
R4 denotes an R7xe2x80x94(n-C1-3-alkyl)-phenyl group, wherein
R7 denotes an amino, C1-6-alkylamino, di-(C1-4-alkyl)-amino, xcfx89-hydroxy-C2-3-alkyl-amino, Nxe2x80x94(C1-3-alkyl)xcfx89-hydroxy-C2-3-alkyl-amino, di-(xcfx89-hydroxy-C2-3-alkyl)-amino or di-(xcfx89-(C1-3-alkoxy)-C2-3-alkyl)-amino group,
or a phenyl group substituted by the group of formula
xe2x80x94N(R12)xe2x80x94COxe2x80x94(CH2)pxe2x80x94R13xe2x80x83xe2x80x83(IV),
wherein R12, p and R13 are as hereinbefore defined,
the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof.
A second subgroup of particularly preferred compounds of general formula I deserving special mention comprises those wherein
X, R1, R3 and R5 are as hereinbefore defined,
R2 denotes an aminocarbonyl or methylaminocarbonyl group, an ethylaminocarbonyl group optionally substituted in the 2 position of the ethyl group by a hydroxy or C1-3-alkoxy group or, if R4 does not denote an aminosulphonyl-phenyl or Nxe2x80x94(C1-5-alkyl)-C1-3-alkylaminocarbonyl-phenyl group, R2 may also denote a di-(C1-2-alkyl)-aminocarbonyl group and
R4 denotes a R7xe2x80x94(n-C1-3-alkyl)-phenyl group, wherein
R7 denotes an amino, C1-6-alkylamino, di-(C1-4-alkyl)-amino, xcfx89-hydroxy-C2-3-alkyl-amino, Nxe2x80x94(C1-3-alkyl)-xcfx89-hydroxy-C2-3-alkyl-amino, di-(xcfx89-hydroxy-C2-3-alkyl)-amino or di-(xcfx89-(C1-3-alkoxy)-C2-3-alkyl)amino group,
or a phenyl group substituted by the group of formula
xe2x80x83xe2x80x94N(R12)xe2x80x94COxe2x80x94(CH2)pxe2x80x94R13xe2x80x83xe2x80x83(IV),
wherein R12, p and R13 are as hereinbefore defined,
the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof.
Most particularly preferred compounds of general formula I are those wherein
X denotes an oxygen atom,
R1 and R5 each denote a hydrogen atom,
R2 denotes a methoxycarbonyl, ethoxycarbonyl or aminocarbonyl group,
R3 denotes a phenyl group and
R4 denotes a phenyl group monosubstituted by the group R6, wherein
R6 denotes an N-methyl-imidazol-2-yl group,
an unbranched C1-3-alkyl group which is terminally substituted by a C1-4-alkylamino, di-(C1-4-alkyl)-amino, piperidino or 2,6-dimethyl-piperidino group,
a group of formula
xe2x80x94N(R12)xe2x80x94COxe2x80x94(CH2)pxe2x80x94R13xe2x80x83xe2x80x83(IV),
xe2x80x83wherein
R12 denotes a C1-3-alkyl group,
p denotes one of the numbers 1 or 2 and
R13 denotes a di-(C1-3-alkyl)-amino group,
or a group of formula
xe2x80x94N(R14)xe2x80x94(CH2)qxe2x80x94(CO)rxe2x80x94R15xe2x80x83xe2x80x83(V),
xe2x80x83wherein
R14 denotes a C1-3-alkyl-carbonyl or C1-3-alkylsulphonyl group,
q denotes one of the numbers 1, 2 or 3,
r denotes the number 1 or, if q is one of the numbers 2 or 3, r may also denote the number 0 and
R15 denotes a di-(C1-3-alkyl)-amino group,
wherein the saturated alkyl moieties contained in the abovementioned groups which contain more than 2 carbon atoms may be straight-chain or branched, unless otherwise stated,
the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof.
A subgroup of most particularly preferred compounds of general formula I deserving special mention comprises those wherein
X, R1, R3 and R5 are as hereinbefore defined,
R2 denotes a methoxycarbonyl or ethoxycarbonyl group and
R4 denotes a di-(C1-3-alkyl)-amino-C1-3-alkylphenyl group or
a phenyl group substituted by the group of formula
xe2x80x94N(R12)xe2x80x94COxe2x80x94(CH2)pxe2x80x94R13xe2x80x83xe2x80x83(IV),
wherein R12, p and R13 areas hereinbefore defined,
the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof.
The following are mentioned as examples of particularly preferred compounds:
(a) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone,
(b) 3-Z-[(1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone,
(c) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,
(d) 3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone,
(e) 3-Z-[1-(4-((2,6dimethyl-piperidin-1-yl)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone,
(f) 3-Z-[1-(4N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone,
(g) 3-Z-[1-(4-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone,
(h) 3-Z-[1-(4(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone,
(i) 3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,
(j) 3-Z-[1-(4-(N-acetyl-N-dimethylaminocarbonylmethyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,
(k) 3-Z-[1-(4-ethylaminomethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,
(l) 3-Z-[1-(4-(1-methyl-imidazol-2-yl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,
(m) 3-Z-[1-(4N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,
(n) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,
(o) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,
(p) 3-Z-[1-(4-(N-dimethylaminocarbonylmethyl-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,
(q) 3-Z-[1-(4(N-((2-dimethylamino-ethyl)carbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,
(r) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone and
(s) 3-Z-[1-(4-methylaminomethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
the tautomers, the mixtures and the salts thereof.
Another subgroup of compounds of general formula I comprises those wherein X denotes an oxygen or sulphur atom,
R1 denotes a hydrogen atom or a prodrug group such as a C1-4-alkoxycarbonyl or C2-4-alkanoyl group,
R2 denotes a carboxy group, a straight-chain or branched C1-6-alkoxycarbonyl group, a C5-7Cycloalkoxycarbonyl or phenyl-C1-3-alkoxycarbonyl group, an aminocarbonyl or C1-2-alkylaminocarbonyl group or, if R4 does not denote an aminosulphonyl-phenyl or Nxe2x80x94(C1-5-alkyl)-C1-3-alkylaminocarbonyl-phenyl group, a di-(C1-2-alkyl)-aminocarbonyl group,
R3 denotes a hydrogen atom, a C1-6-alkyl, C3-7-cycloalkyl, trifluoromethyl or heteroaryl group,
a phenyl or naphthyl group, a phenyl or naphthyl group mono- or disubstituted by a fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl, C1-3-alkyl or C1-3-alkoxy group, whilst in the event of disubstitution the substituents may be identical or different and wherein the abovementioned unsubstituted as well as the mono- and disubstituted phenyl and naphthyl groups may additionally be substituted
by a hydroxy, hydroxy-C1-3-alkyl or C1-3-alkoxy-C1-3-alkyl group,
by a cyano, carboxy, carboxy-C1-3-alkyl, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylamino-carbonyl or di-(C1-3-alkyl)-aminocarbonyl group,
by a nitro group,
by an amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino or amino-C1-3-alkyl group,
by a C1-3-alkylcarbonylaamino, Nxe2x80x94(C1-3-alkyl)-C1-3-alkyl-carbonylamino, C1-3-alkylcarbonylamino-C1-3-alkyl, Nxe2x80x94(C1-3-alkyl)-C1-3-alkylcarbonylamino-C1-3-alkyl, C1-3-alkyl-sulphonylamino, C1-3-alkylsulphonylamino-C1-3-alkyl, Nxe2x80x94(C1-3-alkyl)-C1-3-alkylsulphonylamino-C1-3-alkyl or aryl-C1-3-alkylsulphonylamino group,
by a cycloalkylamino, cycloalkyleneimino, cycloalkyleneiminocarbonyl, cycloalkyleneimino-C1-3-alkyl, cycloalkyleneiminocarbonyl-C1-3-alkyl or cycloalkyleneiminosulphonyl-C1-3-alkyl group having 4 to 7 ring members in each case, whilst in each case the methylene group in position 4 of a 6 or 7-membered cycloalkyleneimino group may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, xe2x80x94NH or xe2x80x94N(C1-3-alkyl) group,
or by a heteroaryl or heteroaryl-C1-3-alkyl group,
R4 denotes a C3-7-cycloalkyl group,
whilst the methylene group in the 4 position of a 6- or 7-membered cycloalkyl group may be substituted by an amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group or replaced by an xe2x80x94NH or xe2x80x94N(C1-3-alkyl) group,
or a phenyl group substituted by the group R6, which may additionally be substituted by a fluorine, chlorine, bromine or iodine atom, by a C1-5-alkyl, trifluoromethyl, C1-3-alkoxy, carboxy, C1-3-alkoxycarbonyl, aminosulphonyl, nitro or cyano group, wherein
R6 denotes a hydrogen, fluorine, chlorine, bromine or iodine atom,
a cyano, nitro, C1-5-alkyl, C3-7-cycloalkyl, trifluoromethyl, phenyl, tetrazolyl or heteroaryl group,
a C1-3-alkoxy group optionally substituted by 1 to 3 fluorine atoms, a C1-3-alkoxy-C1-3-alkoxy, phenyl-C1-3-alkoxy, amino-C2-3-alkoxy, C1-3-alkylamino-C2-3-alkoxy, di-(C1-3-alkyl)-amino-C2-3-alkoxy, phenyl-C1-3-alkylamino-C2-3-alkoxy, Nxe2x80x94(C1-3-alkyl)-phenyl-C1-3-alkylamino-C2-3-alkoxy, C5 7-cycloalkyleneimino-C2-3-alkoxy or C1-3-alkylmercapto group,
a carboxy, C1-4-alkoxycarbonyl, aminocarbonyl, C1-3-alkylamino-carbonyl, Nxe2x80x94(C1-5-alkyl)-C1-3-alkylaminocarbonyl, phenyl-C1-3-alkylamino-carbonyl, Nxe2x80x94(C1-3-alkyl)phenyl-C1-3-alkylamino-carbonyl, piperazinocarbonyl or Nxe2x80x94(C1-3-alkyl)-piperazinocarbonyl group,
a C1-3-alkylaminocarbonyl or Nxe2x80x94(C1-5-alkyl)-C1-3-alkylaminocarbonyl group wherein an alkyl moiety is substituted by a carboxy or C1-3-alkoxycarbonyl group or is substituted in the 2 or 3 position by a di-(C1-3-alkyl)-amino, piperazino, Nxe2x80x94(C1-3-alkyl)-piperazino or a 4- to 7-membered cycloalkyleneimino group,
a 4- to 7-membered cycloalkyleneimino group, wherein
a methylene group linked to the imino group may be replaced by a carbonyl or sulphonyl group or
the cycloalkylene moiety may be fused to a phenyl ring or
one or two hydrogen atoms may each be replaced by a C1-3-alkyl group and/or
in each case the methylene group in the 4 position of a 6 or 7-membered cycloalkyleneimino group may be substituted by a carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, phenyl-C1-3-alkylamino or Nxe2x80x94(C1-3-alkyl)-phenyl-C1-3-alkylamino group or
may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, xe2x80x94NH, xe2x80x94N(C1-3-alkyl), xe2x80x94N(phenyl), xe2x80x94N(C1-3-alkyl-carbonyl) or xe2x80x94N(benzoyl) group,
a C1-4-alkyl group which may be substituted
by a hydroxy or C1-3-alkoxy group,
by an amino, C1-7-alkylamino, di-(C1-7-alkyl)-amino, di-Nxe2x80x94(C1-3-alkyl)-amino-C2-3-alkylamino, tri-N,N,Nxe2x80x2-C1-3-alkyl)-amino-C2-3-alkylamino, phenylamino, N-phenyl-C1-3-alkyl-amino, phenyl-C1-3-alkylamino, Nxe2x80x94(C1-3-alkyl)-phenyl-C1-3-alkylamino or di-(phenyl-C1-3-alkyl)-amino group,
by a C1-3-alkylcarbonylamino, Nxe2x80x94(C1-3-alkyl)-C1-3-alkylcarbonylamino, C1-3-alkoxycarbonyl-C1-3-alkylamino or Nxe2x80x94(C1-3-alkyl) C1-3-alkoxycarbonyl-C1-3-alkylamino group,
by a C4-7-cycloalkylamino, C4-7-cycloalkyl-C1-3-alkylamino or C4-7-cycloalkenylamino group wherein position 1 of the ring is not involved in the double bond and wherein the abovementioned groups may each additionally be substituted at the amino-nitrogen atom by a C1-3-alkyl group wherein some or all of the hydrogen atoms are replaced by fluorine atoms, by a C5-7-cycloalkyl, C2-4-alkenyl or C1-4-alkyl group,
by a 4- to 7-membered cycloalkyleneimino group, wherein
a methylene group linked to the imino group may be replaced by a carbonyl or sulphonyl group or
the cycloalkylene moiety may be fused to a phenyl group or to an oxazolo, imidazolo, thiazolo, pyridino, pyrazino or pyrimidino group optionally substituted by a fluorine, chlorine, bromine or iodine atom, by a nitro, C1-3-alkyl, C1-3-alkoxy or amino group or
one or two hydrogen atoms may each be replaced by a C1-3-alkyl, C5-7-cycloalkyl or phenyl group and/or
in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be substituted by a hydroxy, carboxy, C1-4-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, phenyl-C1-3-alkylamino or Nxe2x80x94(C1-3-alkyl)-phenyl-C1-3-alkylamino group or
may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, xe2x80x94NH, xe2x80x94N(C1-3-alkyl), xe2x80x94N(phenyl), xe2x80x94N(C1-3-alkyl-carbonyl) or xe2x80x94N(benzoyl) group,
by a carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl or di-(C1-3-alkyl)-aminocarbonyl group or
by a 4- to 7-membered cycloalkyleneiminocarbonyl group,
an amino, pyrrolidino, piperidino, morpholino, benzoylamino or Nxe2x80x94(C1-3-alkyl)-benzoylamino group,
an Nxe2x80x94(C1-3-alkyl)-C2-4-alkanoylamino group which is additionally substituted in the alkyl moiety by a carboxy or C1-3-alkoxycarbonyl group,
a group of formula
xe2x80x94N(R8)xe2x80x94COxe2x80x94(CH2)nxe2x80x94R9xe2x80x83xe2x80x83(II),
xe2x80x83wherein
R8 denotes a hydrogen atom or a C1-3-alkyl group,
n denotes one of the numbers 0, 1, 2 or 3 and
R9 denotes an amino, C1-4-alkylamino, phenylamino, Nxe2x80x94(C1-4-alkyl)-phenylamino, benzylamino, Nxe2x80x94(C1-4-alkyl)-benzylamino or di-(C1-4-alkyl)-amino group, a 4- to 7-membered cycloalkyleneimino group, whilst in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, xe2x80x94NH, xe2x80x94N(C1-3-alkyl), xe2x80x94N(phenyl), xe2x80x94N(C1-3-alkylcarbonyl) or xe2x80x94N(benzoyl) group, or, if n denotes one of the numbers 1, 2 or 3, it may also denote a hydrogen atom,
a group of formula
xe2x80x94N(R10)xe2x80x94(CH2)mxe2x80x94(CO)oxe2x80x94R11xe2x80x83xe2x80x83(III),
xe2x80x83wherein
R10 denotes a hydrogen atom, a C1-3-alkyl group, a C1-3-alkylcarbonyl, arylcarbonyl, phenyl-C1-3-alkylcarbonyl, C1-3-alkylsulphonyl, arylsulphonyl or phenyl-C1-3-alkylsulphonyl group,
m denotes one of the numbers 1, 2, 3 or 4,
o denotes one of the numbers 0 or 1 and
R11 denotes an amino, C1-4-alkylamino, phenylamino, Nxe2x80x94(C1-4-alkyl)-phenylamino, benzylamino, Nxe2x80x94(C1-4-alkyl)-benzylamino or di-(C1-4-alkyl)-amino group, a 4- to 7-membered cycloalkyleneimino group, wherein the cycloalkylene moiety may be fused to a phenyl ring or in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, xe2x80x94NH, xe2x80x94N(C1-3-alkyl), xe2x80x94N(phenyl), xe2x80x94N(C1-3-alkyl-carbonyl) or xe2x80x94N(benzoyl) group, a C1-3-alkoxy group or a di-(C1-4alkyl)-amino-C1-3-alkylamino group optionally substituted in the 1 position by a C1-3-alkyl group,
or an Nxe2x80x94(C1-3-alkyl)-C1-5-alkylsulphonylamino or Nxe2x80x94(C1-3-alkyl)-phenylsulphonylamino group wherein the alkyl moiety is additionally substituted by a cyano or carboxy group,
wherein all the single-bonded or fused phenyl groups contained in the groups mentioned under R6 may be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C1-5-alkyl, trifluoromethyl, C1-3-alkoxy, carboxy, C1-3-alkoxycarbonyl, aminosulphonyl, nitro or cyano groups, wherein the substituents may be identical or different, or two adjacent hydrogen atoms of the phenyl groups may be replaced by a methylenedioxy group,
and
R5 denotes a hydrogen atom or a C1-3-alkyl group,
wherein by an aryl group is meant a phenyl or naphthyl group optionally mono- or disubstituted by a fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl, C1-3-alkyl or C1-3-alkoxy group and
by a heteroaryl group is meant a monocyclic 5- or 6-membered heteroaryl group optionally substituted by a C1-3-alkyl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C1-3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C1-3-alkyl group and an oxygen or sulphur atom or one or two nitrogen atoms, and moreover a phenyl ring may be fused to the abovementioned monocyclic heterocyclic groups via two adjacent carbon atoms,
the saturated alkyl and alkoxy moieties present in the groups defined above which contain more than 2 carbon atoms also include the branched isomers thereof such as, for example, the isopropyl, tert.butyl or isobutyl group, unless otherwise stated, and
additionally any carboxy, amino or imino group present may be substituted by a group which can be cleaved in vivo,
the isomers and the salts thereof.
According to the invention the new compounds are obtained, for example, by the following methods known in principle from the literature:
a. reacting a compound of general formula 
xe2x80x83wherein
X and R3 are as hereinbefore defined,
R2xe2x80x2 has the meanings given for R2 hereinbefore,
R18 denotes a hydrogen atom or a protecting group for the nitrogen atom of the lactam group, wherein one of the groups R2xe2x80x2 and R18 may also denote a bond to a solid phase optionally formed via a spacer and the other one of the groups R2xe2x80x20 and R18 has the abovementioned meanings, and Z1 denotes a halogen atom, a hydroxy, alkoxy or aryl-alkoxy group, e.g. a chlorine or bromine atom, a methoxy, ethoxy or benzyloxy group,
xe2x80x83with an amine of general formula 
xe2x80x83wherein
R4 and R5 are as hereinbefore defined, and if necessary subsequently cleaving any protecting group used for the nitrogen atom of the lactam group or cleaving from a solid phase.
The protecting group for the nitrogen atom of the lactam group may be, for example, an acetyl, benzoyl, ethoxycarbonyl, tert.butyloxycarbonyl or benzyloxycarbonyl group and the solid phase may be a resin such as a 4-(2xe2x80x2,4xe2x80x2-dimethoxyphenylaminomethyl)-phenoxy resin, the bond preferably being formed via the amino group, or a p-benzyloxybenzyl alcohol resin, wherein the bond is conveniently formed via an intermediate member such as a 2,5-dimethoxy-4-hydroxy-benzyl derivative.
The reaction is conveniently carried out in a solvent such as dimethylformamide, toluene, acetonitrile, tetrahydrofuran, dimethylsulphoxide, methylene chloride or mixtures thereof, optionally in the presence of an inert base such as triethylamine, N-ethyl-diisopropylamine or sodium hydrogen carbonate at temperatures between 20 and 175xc2x0 C., whilst any protecting group used can be cleaved at the same time by transamidation.
If Z1 in a compound of general formula VII denotes a halogen atom, the reaction is preferably carried out in the presence of an inert base at temperatures of between 20 and 120xc2x0 C.
If Z1 in a compound of general formula VII denotes a hydroxy, alkoxy or arylalkoxy group, the reaction is preferably carried out at temperatures between 20 and 200xc2x0 C.
If a protecting group used subsequently has to be cleaved, this is conveniently done either hydrolytically in an aqueous or alcoholic solvent, e.g. in methanol/water, ethanol/water, isopropanol/water, tetrahydrofuran/water, dioxan/water, dimethylformamide/water, methanol or ethanol in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide at temperatures between 0 and 100xc2x0 C., preferably at temperatures between 10 and 50xc2x0 C.,
or advantageously by transamidation with an organic base such as ammonia, butylamine, dimethylamine or piperidine in a solvent such as methanol, ethanol, dimethylformamide and the mixtures thereof or in an excess of the amine used, at temperatures between 0 and 100xc2x0 C., preferably at temperatures between 10 and 50xc2x0 C.
Cleaving from any solid phase used is preferably carried out using trifluoroacetic acid and water at temperatures between 0 and 35xc2x0 C., preferably at ambient temperature.
b. In order to prepare a compound of general formula I wherein R2 has the meanings given hereinbefore, with the exception of the carboxy group:
reacting a compound of general formula 
xe2x80x83wherein
R1 and R3 to R5 are as hereinbefore defined, or the reactive derivatives thereof, with a compound of general formula
Hxe2x80x94R19xe2x80x83xe2x80x83(X),
xe2x80x83wherein
R19 denotes a C1-6-alkanol, a C4-7-cycloalkanol or an aromatic alcohol,
a C1-6-alkanol which is terminally substituted in the alkyl moiety by a phenyl, heteroaryl, carboxy, C1-3-alkoxy-carbonyl, aminocarbonyl, C1-3-alkylamino-carbonyl or di-(C1-3-alkyl)-aminocarbonyl group,
a C2-6-alkanol which is terminally substituted in the alkyl moiety by a chlorine atom or a hydroxy, C1-3-alkoxy, amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group,
an amino or methylamino group, an ethylamino group optionally substituted in the 2 position of the ethyl group by a hydroxy or C1-3-alkoxy group or a di-(C1-2-alkyl)amino group.
The esterification or amidation is preferably carried out in a solvent such as methylene chloride, diethylether, tetrahydrofuran, toluene, dioxan, acetonitrile, dimethylsulphoxide or dimethylformamide, optionally in the presence of an inorganic or a tertiary organic base, preferably at temperatures between 20xc2x0 C. and the boiling temperature of the solvent used. The reaction with a corresponding acid is preferably carried out in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionylchloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,Nxe2x80x2-dicyclohexylcarbodiimide, N,Nxe2x80x2-dicyclohexyl-carbodiimide/N-hydroxysuccinimide, N,Nxe2x80x2-dicyclohexyl-carbodiimide/1-hydroxy-benzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate/1-hydroxy-benzotriazole, N,Nxe2x80x2-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, N-methyl-morpholine or triethylamine, conveniently at temperatures between 0 and 150xc2x0 C., preferably at temperatures between 0 and 100xc2x0 C., and the acylation with a corresponding reactive compound such as an anhydride, ester, imidazolide or halide thereof, is optionally carried out in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine or N-methyl-morpholine at temperatures between 0 and 150xc2x0 C., preferably at temperatures between 50 and 100xc2x0 C.
c. In order to prepare a compound of general formula I, wherein R4 denotes a C1-4-alkyl group substituted by the group R7, wherein
R7 denotes an amino, C1-7-alkylamino, di-(C1-7-alkyl)-amino, phenylamino, N-phenyl-C1-3-alkyl-amino, phenyl-C1-3-alkylamino, Nxe2x80x94(C1-3-alkyl)-phenyl-C1-3-alkylamino or di-(phenyl-C1-3-alkyl)-amino group,
a xcfx89-hydroxy-C2-3-alkyl-amino, Nxe2x80x94(C1-3-alkyl)-xcfx89-hydroxy-C2-3-alkyl-amino, di-(xcfx89-hydroxy-C2-3-alkyl)-amino, di-(xcfx89-(C1-3-alkoxy)-C2-3-alkyl)-amino or N-(dioxolan-2-yl)-C1-3-alkyl-amino group,
a C1-3-alkylcarbonylamino-C2-3-alkyl-amino or C1-3-alkylcarbonylamino-C2-3-alkyl-Nxe2x80x94(C1-3-alkyl)-amino group,
a C1-3-alkylsulphonylamino, Nxe2x80x94(C1-3-alkyl)-C1-3-alkylsulphonylamino, C1-3-alkylsulphonylamino-C2-3-alkyl-amino or C1-3-alkylsulphonylamino-C2-3-alkyl-Nxe2x80x94(C1-3-alkyl)-amino group,
a group of formula
xe2x80x94N(R10)xe2x80x94(CH2)mxe2x80x94(CO)oxe2x80x94R11xe2x80x83xe2x80x83(III),
xe2x80x83wherein
R10 denotes a hydrogen atom, a C1-3-alkyl group, a C1-3-alkylcarbonyl, arylcarbonyl, phenyl-C1-3-alkylcarbonyl, C1-3-alkylsulphonyl, arylsulphonyl or phenyl-C1-3-alkylsulphonyl group,
m denotes one of the numbers 1, 2, 3 or 4,
o denotes the number 1 and
R11 denotes an amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, phenylamino, Nxe2x80x94(C1-4-alkyl)-phenylamino, benzylamino, Nxe2x80x94(C1-4-alkyl)-benzylamino,
C1-4-alkoxy or C1-3-alkoxy-C1-3-alkoxy group, a di-(C1-4-alkyl)-amino-C1-3-alkylamino group optionally substituted in the 1 position by a C1-3-alkyl group, or a 4- to 7-membered cycloalkyleneimino group, wherein the cycloalkylene moiety may be fused to a phenyl ring or in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, xe2x80x94NH, xe2x80x94N(C1-3-alkyl), xe2x80x94N(phenyl), xe2x80x94N(C1-3-alkyl-carbonyl) or xe2x80x94N(benzoyl) group,
a C4-7-cycloalkylamino, C4-7-cycloalkyl-C1-3-alkylamino or C4-7-cycloalkenylamino group wherein position 1 of the ring is not involved in the double bond and wherein the abovementioned groups may each additionally be substituted at the amino-nitrogen atom by a C5-7-cycloalkyl, C2-4-alkenyl or C1-4-alkyl group,
or a 4- to 7-membered cycloalkyleneimino group, wherein
the cycloalkylene moiety may be fused to a phenyl group or to an oxazolo, imidazolo, thiazolo, pyridino, pyrazino or pyrimidino group optionally substituted by a fluorine, chlorine, bromine or iodine atom, by a nitro, C1-3-alkyl, C1-3-alkoxy or amino group, and/or
one or two hydrogen atoms may each be replaced by a C1-3-alkyl, C5-7-cycloalkyl or phenyl group and/or
the methylene group in the 3 position of a 5-membered cycloalkyleneimino group may be substituted by a hydroxy, hydroxy-C1-3-alkyl, C1-3-alkoxy or C1-3-alkoxy-C1-3-alkyl group,
in each case the methylene group in the 3 or 4 position of a 6- or 7-membered cycloalkyleneimino group may be substituted by a hydroxy, hydroxy-C1-3-alkyl, C1-3-alkoxy, C1-3-alkoxy-C1-3-alkyl, C1-4-alkoxycarbonyl, aminocarbonyl,
C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, phenyl-C1-3-alkylamino or Nxe2x80x94(C1-3-alkyl)-phenyl-C1-3-alkylamino group or
may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, xe2x80x94NH, xe2x80x94N(C1-3-alkyl-), xe2x80x94N(phenyl), xe2x80x94N(phenyl-C1-3-alkyl-), xe2x80x94N(C1-3-alkyl-carbonyl-), xe2x80x94N(C1-4-alkoxy-carbonyl-), xe2x80x94N(benzoyl-) or xe2x80x94N(phenyl-C1-3-alkyl-carbonyl-) group,
wherein a methylene group linked to an imino-nitrogen atom of the cycloalkyleneimino group may be replaced by a carbonyl or sulphonyl group or in a 5- to 7-membered monocyclic cycloalkyleneimino group or a cycloalkyleneimino group fused to a phenyl group the two methylene groups linked to the imino-nitrogen atom may each be replaced by a carbonyl group:
reacting a compound of general formula 
xe2x80x83wherein
R3, R5 and X are as hereinbefore defined,
R2xe2x80x2 has the meanings given for R2 hereinbefore,
R18 denotes a hydrogen atom or a protecting group for the nitrogen atom of the lactam group, wherein one of the groups R2xe2x80x2 and R18 may also denote a bond to a solid phase optionally formed via a spacer and the other one of the groups R2xe2x80x2 and R18 has the abovementioned meanings, A denotes a C1-4-alkyl group and Z2 denotes a leaving group, for example an alkyl or arylsulphonyloxy group such as the methylsulphonyloxy, ethylsulphonyloxy, p-toluenesulphonyloxy or trifluoromethanesulphonyloxy group, with an amine of general formula
Hxe2x80x94R7,xe2x80x83xe2x80x83(XII),
xe2x80x83wherein
R7, has the meanings given for R7 hereinbefore, and subsequently, if necessary, cleaving any protecting group used for the nitrogen atom of the lactam group, or cleaving from a solid phase.
The reaction is conveniently carried out in a solvent such as methylene chloride, tetrahydrofuran, 1,4-dioxan, toluene, acetonitrile, dimcthylsulphoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone or the mixtures thereof, optionally with the saddition of water as a co-solvent and/or with the addition of an inert auxiliary base, e.g. sodium hydrogen carbonate, pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine, N-ethyldiisopropylamine, N-ethyl-dicyclohexylamine, 1,4-diazabicyclo[2,2,2]octane or 1,8-diazabicyclo[5,4,0]undec-7-ene, at temperatures between xe2x88x9250xc2x0 C. and +100xc2x0 C., preferably between xe2x88x9210xc2x0 C. and +50xc2x0 C., while any protecting group used may be cleaved at the same time by transamidation.
If any protecting group used for the nitrogen atom of the lactam group has to be removed or if the compound has to be cleaved from a solid phase this is carried out as described under method (a) above.
If according to the invention a compound of general formula I is obtained which contains an alkoxycarbonyl group, this may be converted by hydrolysis into a corresponding carboxy compound, or
if a compound of general formula I is obtained which contains an amino or alkylamino group, this may be converted by reductive alkylation into a corresponding alkylamino or dialkylamino compound, or
if a compound of general formula I is obtained which contains an amino or alkylamino group, this may be converted by acylation or sulphonation into a corresponding acyl or sulphonyl compound, or
if a compound of general formula I is obtained which contains a carboxy group, this may be converted by esterification or amidation into a corresponding ester or aminocarbonyl compound, or
if a compound of general formula I is obtained which contains a cycloalkyleneimino group wherein a methylene group is replaced by a sulphur atom, this may be converted by oxidation into a corresponding sulphinyl or sulphonyl compound, or
if a compound of general formula I is obtained which contains a nitro group, this may be converted by reduction into a corresponding amino compound, or
if a compound of general formula I is obtained wherein R4 denotes a phenyl group substituted by an amino, alkylamino, aminoalkyl or N-alkyl-amino group, this may subsequently be converted, by reaction with a corresponding cyanate, isocyanate or carbamoyl halide, into a corresponding urea compound of general formula I, or
if a compound of general formula I is obtained wherein R4 denotes a phenyl group substituted by an amino, alkylamino, aminoalkyl or N-alkyl-amino group, this may subsequently be converted, by reaction with a corresponding compound which transfers the amidino group or by reaction with a corresponding nitrile, into a corresponding guanidino compound of general formula I.
The subsequent hydrolysis is preferably carried out in an aqueous solvent, e.g. in water, methanol/water, ethanol/water, isopropanol/water, tetrahydrofuran/water or dioxan/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide at temperatures between 0 and 100xc2x0 C., preferably at temperatures between 10 and 50xc2x0 C.
The subsequent reductive alkylation is preferably carried out in a suitable solvent such as methanol, methanol/water, methanol/water/ammonia, ethanol, ether, tetrahydrofuran, dioxan or dimethylformamide, optionally with the addition of an acid such as hydrochloric acid in the presence of catalytically activated hydrogen, e.g. hydrogen in the presence of Raney nickel, platinum or palladium/charcoal, or in the presence of a metal hydride such as sodium borohydride, lithium borohydride, sodium cyanoborohydride or lithium aluminium hydride at temperatures between 0 and 100xc2x0 C., preferably at temperatures between 20 and 80xc2x0 C.
The subsequent acylation or sulphonylation is preferably carried out with the corresponding free acid or a corresponding reactive compound such as the anhydride, ester, imidazolide or halide thereof, preferably in a solvent such as methylene chloride, diethylether, tetrahydrofuran, toluene, dioxan, acetonitrile, dimethylsulphoxide or dimethylformamide, optionally in the presence of an inorganic or tertiary organic base at temperatures between xe2x88x9220 and 200xc2x0 C., preferably at temperatures between 20xc2x0 C. and boiling temperature of the solvent used. The reaction with the free acid may optionally be carried out in the presence of an acid-activating agent or a dehydrating agent, e.g. in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,Nxe2x80x2-dicyclohexylcarbodiimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/1-hydroxy-benzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate/1-hydroxy-benzotriazole, N,Nxe2x80x2-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylamino-pyridine, N-methyl-morpholine or triethylamine, conveniently at temperatures between 0 and 150xc2x0 C., preferably at temperatures between 0 and 100xc2x0 C. The reaction with a corresponding reactive compound may optionally be carried out in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine, N-methyl-morpholine or pyridine or by using an anhydride in the presence of the corresponding acid at temperatures between 0 and 150xc2x0 C., preferably at temperatures between 50 and 100xc2x0 C.
The subsequent esterification or amidation is conveniently carried out by reacting a corresponding reactive carboxylic acid derivative with a corresponding alcohol or amine as described hereinbefore.
The subsequent oxidation of the sulphur atom is preferably carried out in a solvent or mixture of solvents, e.g. in water, water/pyridine, acetone, methylene chloride, acetic acid, acetic acid/acetic anhydride, dilute sulphuric acid or trifluoroacetic acid, usefully at temperatures of between xe2x88x9280 and 100xc2x0 C. depending on the oxidising agent used.
In order to prepare a corresponding sulphinyl compound of general formula I the oxidation is expediently carried out with one equivalent of the oxidising agent used, e.g. with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or formic acid at 0 to 20xc2x0 C. or in acetone at 0 to 60xc2x0 C., with a peracid such as perforrnic acid in glacial acetic acid or trifluoroacetic acid at 0 to 50xc2x0 C. or with m-chloroperbenzoic acid in methylene chloride, chloroform or dioxan at xe2x88x9220 to 80xc2x0 C., with sodium metaperiodate in aqueous methanol or ethanol at xe2x88x9215 to 25xc2x0 C., with bromine in glacial acetic acid or aqueous acetic acid optionally in the presence of a weak base such as sodium acetate, with N-bromosuccinimide in ethanol, with tert.butyl hypochlorite in methanol at xe2x88x9280 to xe2x88x9230xc2x0 C., with iodobenzodichloride in aqueous pyridine at 0 to 50xc2x0 C., with nitric acid in glacial acetic acid at 0 to 20xc2x0 C., with chromic acid in glacial acetic acid or in acetone at 0 to 20xc2x0 C. and with sulphuryl chloride in methylene chloride at xe2x88x9270xc2x0 C., the resulting thioether-chlorine complex is expediently hydrolysed with aqueous ethanol.
In order to prepare a sulphonyl compound of general formula I the oxidation is expediently carried out starting from a corresponding sulphinyl compound with one or more equivalents of the oxidising agent used or starting from a corresponding mercapto compound, expediently with two or more equivalents of the oxidising agent used, e.g. with hydrogen peroxide in glacial acetic acid/acetic anhydride, trifluoroacetic acid or in formic acid at 20 to 100xc2x0 C. or in acetone at 0 to 60xc2x0 C., with a peracid such as performic acid or m-chloroperbenzoic acid in glacial acetic acid, trifluoroacetic acid, methylene chloride or chloroform at temperatures between 0 and 60xc2x0 C., with nitric acid in glacial acetic acid at 0 to 20xc2x0 C., with chromic acid, sodium periodate or potassium permanganate in acetic acid, water/sulphuric acid or in acetone at 0 to 20xc2x0 C.
The subsequent reduction of a nitro group is preferably carried out by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal or Raney nickel in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid or glacial acetic acid at temperatures of between 0 and 50xc2x0 C., but preferably at ambient temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar.
The subsequent preparation of a corresponding urea compound of general formula I is conveniently carried out with an inorganic cyanate or a corresponding isocyanate or carbamoylchloride, preferably in a solvent such as dimethylformamide and optionally in the presence of a tertiary organic base such as triethylamine at temperatures between 0 and 50xc2x0 C., preferably at ambient.
The subsequent preparation of a corresponding guanidino compound of general formula I is conveniently carried out by reacting with a compound which transfers the amidino group such as 3,5-dimethylpyrazole-1-carboxylic acid amidine, preferably in a solvent such as dimethylformamide and optionally in the presence of a tertiary organic base such as triethylamine at temperatures of between 0 and 50xc2x0 C., preferably at ambient temperature.
In the reactions described hereinbefore, any reactive groups present such as carboxy, hydroxy, amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
For example, a protecting group for a carboxyl group may be a trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group and
protecting groups for a hydroxy, amino, alkylamino or imino group may be an acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino group, a phthalyl group.
Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxan/water, in the presence of a acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, at temperatures between 0 and 100xc2x0 C., preferably at temperatures between 10 and 50xc2x0 C.
However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid or glacial acetic acid at temperatures between 0 and 50xc2x0 C., but preferably at ambient temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar.
A methoxybenzyl group may also be cleaved in the presence of an oxidising agent such as cerium(IV)anmmonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile/water at temperatures of between 0 and 50xc2x0 C., but preferably at ambient temperature.
A 2,4dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisole.
A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxan, ethyl acetate or ether.
A phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxan at temperatures between 20 and 50xc2x0 C.
Moreover, chiral compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers.
Thus, for example, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and Eliel E. L. in xe2x80x9cTopics in Stereochemistryxe2x80x9d, Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
The enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the mixture of diastereomeric salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, N-acetylglutarnic acid, aspartic acid, N-acetylaspartic acid or quinic acid. An optically active alcohol may be for example (+)- or (xe2x88x92)-menthol and an optically active acyl group in arnides, for example, may be a (+)- or (xe2x88x92)-menthyloxycarbonyl group.
Furthermore, the compounds of formula I obtained may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid or methanesulphonic acid.
Moreover, if the new compounds of formula I thus obtained contain a carboxy group, they may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof. Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
The compounds of general formulae VII to XII used as starting materials are known from the literature in some cases or may be obtained by methods known from the literature or may be obtained by the methods described hereinbefore and in the Examples. For example, the compounds of general formula VI are described in German Patent Application 198 24 922.5.
Moreover, the compounds of general formula XI may be obtained from the compounds of general formula I wherein R4 denotes a C1-4-alkyl-phenyl group substituted in the alkyl moiety by a hydroxy group, for example, by reacting with alkyl- or arylsulphonyl-chlorides.
As already mentioned, the new compounds of general formula I wherein R1 denotes a hydrogen atom or a prodrug group have valuable pharmacological properties, particularly inhibitory effects on various kinases, especially on receptor-tyrosine kinases such as VEGFR2, PDGFRxcex1, PDGFRxcex2, FGFR1, FGFR3, EGFR, HER2, IGF1R and HGFR, as well as on complexes of CDK""s (Cyclin Dependent Kinases) such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9 with their specific cyclins (A, B1, B2, C, D1, D2, D3, E, F, G1, G2, H, I and K) and on viral cyclin, on the proliferation of cultivated human cells, particularly endothelial cells, e.g. in angiogenesis, but also on the proliferation of other cells, particularly tumour cells.
The biological properties of the new compounds were tested by the following standard procedure, as follows:
Human umbilical endothelial cells (HUVEC) were cultivated in IMDM (Gibco BRL), supplemented with 10% foetal calf serum (FBS) (Sigma), 50 xcexcM of xcex2-mercaptoethanol (Fluka), standard antibiotics, 15 xcexcg/ml of endothelial cell growth factor (ECGS, Collaborative Biomedical Products) and 100 xcexcg/ml of heparin (Sigma) on gelatine-coated culture dishes (0.2% gelatine, Sigma) at 37xc2x0 C., under 5% CO2 in a water-saturated atmosphere.
In order to investigate the inhibitory activity of the compounds according to the invention the cells were starved for 16 hours, i.e. kept in culture medium without growth factors (ECGS+heparin). The cells were detached from the culture dishes using trypsin/EDTA and washed once in serumontaining medium. Then they were seeded out in amounts of 2.5xc3x97103 cells per well.
The proliferation of the cells was stimulated with 5 ng/ml of VEGF165 (vascular endothelial growth factor; H. Weich, GBF Braunschweig) and 10 xcexcg/ml of heparin. As a control, 6 wells in each dish were not stimulated.
The compounds according to the invention were dissolved in 100% dimethylsulphoxide and added to the cultures in various dilutions in triplicate, the maximum dimethyl sulphoxide concentration being 0.3%.
The cells were incubated for 76 hours at 37xc2x0 C., then for a further 16 hours 3H-thymidine (0.1 xcexcCi/well, Amersham) was added in order to determine the DNA synthesis. Then the radioactively labelled cells were immnobilised on filter mats and the radioactivity incorporated was measured in a xcex2-counter. In order to determine the inhibitory activity of the compounds according to the invention the mean value of the non-stimulated cells was subtracted from the mean value of the factor-stimulated cells (in the presence or absence of the compounds according to the invention).
The relative cell proliferation was calculated as a percentage of the control (HUVEC without inhibitor) and the concentration of active substance which inhibits the proliferation of the cells by 50% (IC50) was determined.
The test results of the following compounds (a) to (s) of general formula I are given by way of example:
(a) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone,
(b) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone,
(c) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,
(d) 3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone,
(e) 3-Z-[1-(4-((2,6-dimethyl-piperidin-1-yl)-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone,
(f) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone,
(g) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone,
(h) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone,
(i) 3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,
(j) 3-Z-[1-(4-(N-acetyl-N-dimethylaminocarbonylmethyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,
(k) 3-Z-[1-(4-ethylaminomethyl-anilino)-1-phenyl-methylene]-6methoxycarbonyl-2-indolinone,
(l) 3-Z-[1-(4-(1-methyl-imidazol-2-yl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,
(m) 3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,
(n) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,
(o) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6methoxycarbonyl-2-indolinone,
(p) 3-Z-[1-(4-(N-dimethylaminocarbonylmethyl-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,
(q) 3-Z-[1-(4-(N-((2-dimethylamino-ethyl)-carbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,
(r) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone and
(s) 3-Z-[1-(4methylaminomethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone.
The following Table contains the results found:
In view of their inhibitory effect on the proliferation of cells, particularly endothelial cells and tumour cells, the compounds of general formula I are suitable for treating diseases in which the proliferation of cells, particularly endothelial cells, plays a part.
Thus, for example, the proliferation of endothelial cells and the concomitant neovascularisation constitute a crucial stage in tumour progression (Folkman J. et al., Nature 339, 58-61, (1989); Hanahan D. and Folkman J., Cell 86, 353-365, (1996)). Furthermore, the proliferation of endothelial cells is also important in haemangiomas, in metastasisation, rheumatoid arthritis, psoriasis and ocular neovascularisation (Folkman J., Nature Med. 1, 27-31, (1995)). The therapeutic usefulness of inhibitors of endothelial cell proliferation was demonstrated in the animal model for example by O""Reilly et al. and Parangi et al. (O""Reilly M. S. et al., Cell 88, 277-285, (1997); Parangi S. et al., Proc Natl Acad Sci USA 93, 2002-2007, (1996)).
The compounds of general formula I, their tautomers, their stereoisomers or the physiologically acceptable salts thereof are thus suitable, for example, for treating tumours (e.g. plate epithelial carcinoma, astrocytoma, Kaposis sarcoma, glioblastoma, lung cancer, bladder cancer, carcinoma of the neck, melanoma, ovarian cancer, prostate cancer, breast cancer, small-cell lung cancer, glioma, colorectal carcinoma, urogenital cancer and gastrointestinal carcinoma as well as haematological cancers, such as multiple myeloma), psoriasis, arthritis (e.g. rheumatoid arthritis), haemangioma, angiofibroma, eye diseases (e.g. diabetic retinopathy), neovascular glaucoma, kidney diseases (e.g. glomerulonephritis), diabetic nephropathy, malignant nephrosclerosis, thrombic microangiopathic syndrome, transplant rejections and glomerulopathy, fibrotic diseases (e.g. cirrhosis of the liver), mesangial cell proliferative diseases, arteriosclerosis and damage to the nerve tissue and also for inhibiting the reocclusion of blood vessels after treatment with a balloon catheter, in vascular prosthetics or after the insertion of mechanical devices for keeping blood vessels open (e.g. stents), or other diseases in which cell proliferation or angiogenesis are involved.
By reason of their biological properties the compounds according to the invention may be used on their own or in conjunction with other pharmacologically active compounds, for example in tumour therapy, in monotherapy or in conjunction with other anti-tumour therapeutic agents, for example in combination with topoisomerase inhibitors (e.g. etoposide), mitosis inhibitors (e.g. vinblastin, taxol), compounds which interact with nucleic acids (e.g. cis-platin, cyclophosphamide, adriamycin), hormone antagonists (e.g. tamoxifen), inhibitors of metabolic processes (e.g. 5-FU etc.), cytokines (e.g. interferons), kinase inhibitors, antibodies, or in conjunction with radiotherapy, etc. These combinations may be administered either simultaneously or sequentially.
For pharmaceutical use the compounds according to the invention are generally used for warm-blooded vertebrates, particularly humans, in doses of 0.01-100 mg/kg of body weight, preferably 0.1-20 mg/kg. For administration they are formulated with one or more conventional inert carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof in conventional galenic preparations such as plain or coated tablets, capsules, powders, injectable solutions, ampoules, suspensions, solutions, sprays or suppositories.
The Examples which follow are intended to illustrate the invention:
Abbreviations used:
FMOC=9-fluorenylmethoxycarbonyl
HOBt=1-hydroxy-1H-benzotriazole
TBTU=O-benzotriazol-1-yl-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium-tetrafluoroborate
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene
Preparation of the starting compounds: